A CHK1-mediated phosphorylation switch suppresses human Topoisomerase 1-associated genomic instability - PubMed
3 days ago
- #genomic instability
- #TOP1
- #CHK1 phosphorylation
- CHK1-mediated phosphorylation of TOP1 at Serine-320 regulates its religation activity, limiting steady-state TOP1 cleavage complexes (TOP1ccs) under physiological conditions.
- Defective phosphorylation at S320 leads to impaired replication-fork progression, causing DNA double-strand breaks, R-loop stabilization, and genomic instability.
- The study reveals a distinct mechanism for TOP1cc stabilization that evades proteasomal and autophagic pathways but is susceptible to removal by CtIP, SPRTN, and p97.
- This regulatory pathway underscores CHK1's role in directly controlling TOP1cc dynamics, with implications for genomic integrity and sensitivity to TOP1 poisons in chemotherapy.